Project Summary/Abstract Less than 1% of hospitalized victims of spinal cord injury (SCI) experience full recovery by the time of discharge, which reflects the human spinal cord?s inability to regenerate and an absence of therapies to induce regeneration after SCI. Non-mammalian animal models such as lampreys, newts, and zebrafish readily regenerate tissues; however, the phylogenetic gap between non-mammalian species and mammals limits the ability of researchers to translate regenerative targets into therapeutics for human SCI. A mammalian model with enhanced spinal regeneration would serve as a powerful tool to identify targets and provide a roadmap for inducing mammalian regeneration after SCI. The genus Acomys consists of mammals closely related to humans and the laboratory mouse (genus Mus). Acomys exhibit scar free regeneration of nerves, muscle, cartilage, adipose tissue, glands, follicles, and skin, and enhanced recovery from muscle and kidney injury. Importantly, Acomys mount inflammatory and fibrotic responses to injury that are unique from those of non-regenerating Mus, and are required for Acomys regeneration. SCI results in robust inflammatory and fibrotic injury in current non-regenerating animal models and affects SCI progression and repair, but these responses have not been examined in Acomys following SCI. I hypothesize that Acomys will exhibit pro-regenerative inflammatory and scarring responses to SCI and functional regeneration of damaged spinal pathways. Using histological and biochemical approaches, Aim 1 of this proposal will investigate spatiotemporal differences in the inflammatory and fibrotic response of Acomys and Mus. Results of this aim will identify if Acomys and Mus injury responses differ following SCI. Aim 2 will use in vitro methods to test species differences in intrinsic neurite outgrowth potential and in vivo methods to test species differences in functional axon regeneration following SCI. While Acomys respond to other injuries with pro-regenerative injury responses that ultimately result in regeneration, these experiments will be the first to directly test the Acomys ability to mount pro-regenerative injury responses in the spinal cord and will establish Acomys ability to regenerate after SCI. This proposal will establish the utility of Acomys as a novel mammalian model of SCI. A mammalian model of SCI with spinal regeneration would be a powerful tool to identify translatable therapeutic targets and provide a roadmap for inducing regeneration in human SCI patients.